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Hemoglobinopathies
- 1. Hemoglobinopathies Moderator – Dr.Sunil Mendhiratta By – Dr. Aftab Ahmad
- 2. Altered structure,function, or production. Usually inherited. Range in severity from asymptomatic laboratory abnormalities to death in utero. Different hemoglobins are produced during embryonic, fetal, and adult life.
- 3. Hemoglobin HbA1 (α2β2)‐ major adult ( 1st appear at 1 month of age ) HbA2 (α2δ2)‐minor HbF (α2γ2) – fetal Properties of adult Hb RBC can alter shape ( deformability ) Can bind upto 4, O2 molecule 2α chains ( 141 amino acids) & 2β chains (146 amino acids). Unpaired globin precipitates, forming inclusions that damage the cell. Bind O2 efficiently & retain at high O2 tension (alveolus). Release at low O2 tension(tissue).
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- 5. Properties of fetalHb It has α2γ2 chains It has high O2 affinity As a consequence, fetal hemoglobin can bind oxygen more efficiently than can adult hemoglobin. This small difference in oxygen affinity mediates the transfer of oxygen from the mother to the fetus Within the fetus, the myoglobin of the fetal muscles has an even higher affinity for oxygen, so oxygen molecules pass from fetal hemoglobin for storage and use in the fetal muscles In the placenta there is net flow of O2 from mother to fetus
- 6. Classification of hemoglobinopathies 1)Structural hemoglobinopathies— hemoglobins with altered amino acid sequences eg HbS 2) Thalassemias—defective biosynthesis of globin chains 3) Thalassemic hemoglobin variants—structurally abnormal Hb associated with co‐inherited thalassemic phenotype 4) Hereditary persistence of fetal hemoglobin 5) Acquired hemoglobinopathies A. Methemoglobin B. Sulfhemoglobin C. Carboxyhemoglobin
- 7. Sicke cell disease Mutation in β globin gene that changes sixth amino acid from glutamic acid to valine Sickle cell anemia is HbSS – when both β globin have sickle cell mutation Sickle cell disease refers to pt of sickle cell anemia , HbS,compound heterozygote where one chain have SC mutation and other is HbC, β- thalassemia , HbD, HbO. In normal RBC Hb molecule do not interact with each other ,whereas in SC mutation Hb molecule are now interact with each other forming a rigid molecule in deoxygenated state that gives its chachecteristic appearance “sickeled shaped” Lung is the only organ capable of reversing the polymer so any disease of lung can compromise the degree of reversibility SC RBC are less deformable and more prone for hemolysis.
- 8. Sickling occursmost commonly in post capillary venules SCD is also an inflammatory disease ( increase TLC and cytokines) Factors increasing sickling are a) Hypoxia b) Low PH c) Fever d) Infection e) Excess exercise f) Anxiety , Dehydration g) Exposure to cold h) Swimming for prolonged hours
- 9. Clinical feature Fever& Bacteremia – because of splenic infarction by 6 mo of age , risk of encapsulated organism infection like S.pneumoniae , H.influenzae type b, N.meningitides. Aplastic Crisis –Human parvovirus B19 infection causing profound reticulocytopenia Splenic Sequestration – As a result of trapping of blood in spleen causing • Rapid enlargement of spleen causing left sided abdominal pain • Profound anemia Sequestration may be triggered by Fever, Bacteremia, or viral infection Treatment- Isotonic fluid , Blood transfusion Blood transfusion is to be given by 5ml/kg because of the risk of hyperviscosity syndrome and Autotranfusion
- 10. Dactylitis orHand Foot Syndrome –Either symmetrical or unilateral painful swelling of hands, and / or feet Destructive changes and periosteal reaction
- 11. Acute vasoocclusivepain- can occur in any part of the body but most often occurs in the Chest, Abdomen, or Extremities These painful episodes are often abrupt and cause disruption of daily life activities Because blood flow is disrupted in the microvasculature by sickled cells, resulting in tissue ischemia Treatment- NSAIDs, Acetamenophen, Hydrocodone Osteomyelitis- Both Salmonella spp. and S. aureus cause osteomyelitis in children with sickle cell anemia, which is often in the diaphysis of long bones (in contrast to children without sickle cell anemia where osteomyelitis is in the metaphyseal region of the bone). Avascular necrosis- Causes of both acute and chronic pain Most common site is femoral head , other site is humeral head and mandible Manage by opioids Blood transfusion is not effective in abating acute or chronic pain
- 12. Priapism- Itis defined as an unwanted painful erection of the penis. Priapism occurs in 2 patterns a) Prolonged- lasting for more than 4 hr b) Stuttering-with brief episodes that resolve spontaneously but may occur in clusters and herald a prolonged event Most episodes occur between 3 a.m. and 9 a.m. Recurrent prolonged episodes of priapism are associated with impotence. Acutely, supportive therapy, such as a hot shower, short aerobic exercise, or pain medication, is commonly used by patients at home Prolonged episode lasting >4 hr should be treated by aspiration of blood from the corpora cavernosa followed by irrigation with dilute epinephrine to produce immediate and sustained detumescence Simple blood transfusion and exchange transfusion has been proposed for the acute treatment of priapism
- 13. Neurologic complications-Ranging from acute ischemic stroke with focal neurologic deficit to clinically silent abnormalities Other neurologic complications include headaches, seizures, cerebral venous thrombosis and posterior reversible encephalopathy syndrome (PRES) For patients presenting with acute focal neurologic deficit oxygen administration to keep oxygen saturations >96% and simple blood transfusion within1 hr of presentation with a goal of increasing the hemoglobin to a maximum of 10 g/dL is warranted. Transcranial Doppler ultrasonography (TCD) assessment of the blood velocity in the terminal portion of the internal carotid and the proximal portion of the middle cerebral artery. Children with sickle cell anemia with an elevated time-averaged mean maximum (TAMM) blood-flow velocity >200 cm/sec are at increased risk for a cerebrovascular event.
- 14. Lung disease-ACSrefers to a life-threatening pulmonary complication of sickle cell disease defined as a new radiodensity on chest radiography plus any 2 of the following: fever, respiratory distress, hypoxia, cough, or chest pain ACS may progress rapidly from a simple infiltrate to extensive infiltrates and a pleural effusion Continued pulse oximetry and frequent clinical exams are required, and repeat chest x-rays are indicated for progressive hypoxia, dyspnea, tachypnea, and other signs of respiratory distress Cause of ACS a) Infection -most common pathogens are S. pneumoniae, Mycoplasma pneumoniae,and Chlamydia sp b) Fat Emboli-arising from infarcted bone marrow Management is by Opioids and use of an incentive spirometer at 10-12 breaths every 2 hr can significantly reduce the frequency of subsequent acute chest pain episodes Since there is clinical overlap between pneumonia and ACS all episodes are treated with IV Antibiotics
- 15. Blood transfusiontherapy using either simple or exchange transfusion is the only method to abort a rapidly progressing episode of ACS Renal Disease and Enuresis-Seven sickle cell disease nephropathies have been identified: (1) Gross hematuria (2) Papillary necrosis (3) Nephrotic syndrome (4) Renal infarction (5) Hyposthenuria (6) Pyelonephritis (7) Renal medullary carcinoma Presence of nocturnal enuresis occurring in children with sickle cell anemia is troublesome to affected children and their parents. The overall prevalence of enuresis is 33%
- 16. Cognitive andPsychological Complications-One of main reason behind the low high school graduation rate is that approximately a third of children with sickle cell anemia have had a cerebral infarct—either silent cerebral infarcts or overt strokes.
- 17. Diagnosis Thin layer/isoelectricfocusing and high-performance liquid chromatography (HPLC) is most commonly used in newborn screening A confirmatory step is recommended, with all patients who have initial abnormal screens being retested during the first clinical visit and after 6 mo of age to determine the final hemoglobin phenotype The hemoglobin with the greatest quantity is reported first, followed by other hemoglobins in order of decreasing quantity.
- 18. THERAPEUTIC CONSIDERATIONS 1) Hydroxyurea-a myelosuppressive agent, is the only drug proven effective in reducing the frequency of painful episodes Hydroxyurea alone is inferior to transfusion therapy for secondary stroke prevention in patients who do not have contraindications to ongoing transfusions The starting dose of hydroxyurea is 15-20 mg/kg given once daily, with an incremental dosage increase every 8 wk of 5 mg/kg, and if no toxicities occur, up to a maximum of 35 mg/kg per dose. Achievement of the therapeutic effect of hydroxyurea can require several months
- 19. 2) Hematopoietic StemCell Transplantation-The only cure for sickle cell anemia is transplantation with human leukocyte antigen (HLA)–matched hematopoietic stem cells from a sibling or unrelated donor. The most common indications for transplant are recurrent ACS, stroke and abnormal TCD 3) Red blood cell transfusions-are frequently used in the management of children with sickle cell anemia, both in the treatment of acute complications such as ACS, aplastic crisis, splenic sequestration, and acute stroke, and to prevent surgery-related ACS Patients with sickle cell disease are at increased risk of developing alloantibodies to less-common red cell surface antigens after receiving even a single transfusion. Therefore in addition to standard cross-matching for major blood group antigens (A, B, O, RhD), more extended matching should be performd for C-, E-, and Kell-antigen
- 20. There are3 methods of blood transfusion therapy that are used a) Automated erythrocytapheresis, b) Manual exchange transfusion c) Simple transfusion. 4) Excessive Iron Stores-Develop after 100 mL/kg of red cell transfusion or about 10 transfusions. Ferritin measurements have significant limitations in their ability to estimate iron stores MRI of the liver has proven to the most effective and common approach for assessment of iron stores. Iron chelators used are Deferoxamine, Deferasirox, Deferiprone
- 21. 5) ANTICIPATORY GUIDANCE a.Spleen Palpation-Splenomegaly is a common complication of sickle cell anemia and splenic sequestration can be life-threatening b. Prophylactic Penicillin-Children with sickle cell anemia should receive prophylactic oral penicillin until at least 5 yr of age c. Immunizations- Pneumococcal and meningococcal vaccinations. d. Transcranial Doppler Ultrasound e. Retinopathy f. Echocardiography
- 22. Thalassemia The thalassemiasare a group of congenital anemias that have in common deficient synthesis of one or more of the globin subunits of the normal human hemoglobins (Hbs). Cooley & Lee in 1925 first described thalassemia as a clinical entity
- 23. Prevalence & Geographicdistribution Most prevalent genetic disorder in the world 29.7 million carriers in India Mumbai 2.7% Delhi 6.6% Kolkata 10.2% Higher prevalance in certain communities Sindhis 12.4% Lohana Gujratis 13.6 %. Reason is attributed to intra-caste & intra-community marriages
- 25. β- Thalessemia syndromes Result from a decrease in β globin chains with a relative excess of α globin chains. β0 thalassemia mutation- no β globin chain production β+ thalassemia mutation- decreased amount of normal β globin production β Thalessemia major: β- refers to the severe β thalassemia patient who requires early transfusion therapy and often is homozygous for β0 mutations. β Thalessemia intermedia: patient with a less-severe clinical phenotype, usually does not require transfusion therapy in childhood. Many have at least 1 β+ thalassemia mutation β Thalassemia Carriers: people with a single β-globin mutation are generally asymptomatic, except for microcytosis and mild anemia.
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- 27. α Thalessemia Syndromes There is an absence or reduction in α-globin production. Normal individuals have 4 α-globin genes. The more genes affected, the more severe the disease. α0-mutation indicates no α-chains produced from that gene. α+ mutation produces a decreased amount of α-globin chain.
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- 29. Epidemiology There are>200 different mutations resulting in absent or decreased globin production. Although most are rare, the 20 most common abnormal alleles constitute 80% of the known thalassemias worldwide 3% of the world’s population carries alleles for β-thalassemia In Southeast Asia 5-10% of the population carry alleles for α-thalassemia.
- 30. Pathophysiology: β thalessemias Two related features contribute to the sequelae of β-thalassemia major: inadequate β-globin chain production α-globin chains are in excess to non–α-globin chains, and α globin tetramers (α4) are formed and appear as red cell inclusions. Free α-globin chain inclusions precipitate in red cell precursors, damage the red cell membrane, shorten red cell survival leading to anemia and increased erythroid production. Because the β0-thalassemia patient cannot make HbA, the α-chains combine with γ-chains, resulting in HbF (α2γ2) being the dominant hemoglobin. δ-Chain synthesis is not usually affected, therefore patients have a relative or absolute increase in HbA2 production (α2δ2).
- 31. Pathophysiology: α thalessemias Reduced copy numbers of α-globin genes produce successively more severe effects. Most people have four copies of the α-globin gene (αα/αα). People with three copies (αα/α-) are healthy; those with two (whether the phase is α-/α- or αα/--) suffer mild α-thalassemia. Those with only one gene (α-/--) have severe disease, while lack of all four α genes (--/--) causes lethal hydrops fetalis. Excess of β- and γ-globin chains are produced. They form Bart haemoglobin (γ4) in fetal life and HbH (β4) after birth. These tetramers are non-functional with very high oxygen affinity.
- 32. Homozygous β-thalassemia (Thalassemia major,Cooley anemia) CLINICAL FEATURES Depending on the mutation and degree of fetal hemoglobin production, transfusions in β-thalassemia major are necessary beginning in the 2nd mo to 2nd yr of life, but rarely later. The classic presentation of children with severe disease includes: Thalassemic facies (maxilla hyperplasia, flat nasal bridge, frontal bossing) Pathologic bone fractures Marked hepatosplenomegaly, hypersplenism and cachexia Chronic anemia even without transfusion exposure leads to increase in iron absorption from G.I tract and secondary hemosiderosis.
- 33. Homozygous β-thalassemia (Thalassemia major,Cooley anemia) CLINICAL FEATURES cont… Each mL of packed red cells contains 1 mg of iron. Physiologically, there is no mechanism to eliminate excess body iron. Iron is initially deposited in the liver. Liver hemosiderosis after 1 yr of chronic transfusion therapy and is followed by iron deposition in the endocrine system. Endocrine manifestations: hypothyroidism, hypogonadotrophic gonadism, growth hormone deficiency, hypoparathyroidism, and diabetes mellitus. After 10 yr of transfusion, cardiac dysfunction secondary to hemosiderosis begins and is a major cause of mortality.
- 34. Homozygous β-thalassemia (Thalassemia major,Cooley anemia) Laboratory Findings There is anemia after the newborn period. Microcytosis (MCV), hypochromia (MCH), and targeting characterize the red cells. Nucleated red cells, marked anisopoikilocytosis, and a relative reticulocytopenia are typically seen. The unconjugated serum bilirubin level is usually elevated. Elevated serum ferritin and transferrin saturation. Bone marrow hyperplasia can be seen on radiographs. Newborn screening techniques such as hemoglobin electrophoresis is not definitive. DNA diagnosis of the β-thalassemia mutation can also be done.
- 35. Ineffective erythropoiesis ina 3 yr old patient who has β- thalassemia major and has not received a transfusion. • A, Massive widening of the diploic spaces of the skull as seen on MRI. • B, Radiographic appearance of the trabeculae as seen on plain radiograph. • C, Obliteration of the maxillary sinuses with hematopoietic tissue as seen on CT scan.
- 36. Management and treatmentof thalassemia Transfusion Therapy Of patients with homozygous β0-thalassemia, 15-20% may have a clinical course that is phenotypically consistent with thalassemia intermedia. In contrast, 25% of patients with homozygous β+-thalassemia, may become transfusion- dependent thalassemia major. Patients should receive red cells depleted of leukocytes and matched for, at least, D, C, c, E, e, and Kell antigens. Cytomegalovirus-negative units are indicated in stem cell transplantation candidates. Transfusions generally given at intervals of 3-4 wk, goal is to maintain a pretransfusion HB level of 9.5-10.5 g/dL. Monitor for transfusion-associated infections (hepatitis A, B, C, HIV), alloimmunization, annual blood transfusion requirements, and transfusion reactions.
- 37. Management and treatmentof thalassemia Iron Overload Monitoring Serial serum ferritin levels are a useful screening technique in assessing iron balance trends. Ferritin may not accurately predict quantitative iron stores. Quantitative liver iron can be measured by liver biopsy. Quantitative liver iron by approved MRI technology is the best noninvasive indicator of total-body iron stores. Quantitative cardiac iron, determined by T2 MRI cardiac software, should be obtained after 7 yr of transfusion therapy.
- 38. Management and treatmentof thalassemia Chelation therapy Significant iron overload occurs after 1 yr of transfusion therapy and correlates with serum ferritin >1,000 ng/mL and/or a liver iron of >2,500 μg/g dry weight. There are 3 available iron chelators: Deferoxamine: It requires s.c, or i.v, (half-life <30 min) necessitating administration of at least 8 hr daily, 5-7 days/wk. Initially started at 20 mg/kg and can be increased to 60 mg/kg in heavily iron-overloaded patients. Deferasirox: Given orally. Requires once-a-day administration of a dispersible tablet in water (half life >16hr). Initial dose is 20 mg/kg with gradual escalation to 30 mg/kg. Deferiprone: Oral iron chelator. Has a half-life of 3 hr and requires 25 mg/kg 3 times a day. May be more effective than other chelators in reducing cardiac hemosiderosis. Combination therapy with two chelators may be needed in some patients.
- 39. Management and treatmentof thalassemia Hydroxyurea Hydroxyurea, a DNA antimetabolite, increases stress erythropoiesis, which results in increased HbF production. It has been most successfully used in sickle cell disease and in some patients with β thalassemia intermedia. Studies in β-thalassemia major are limited. In general, there appears to be a mean increase in haemoglobin of 1 g (range: 0.1-2.5 g). The initial starting dose for thalassemia intermedia is 10 mg/kg.
- 40. Management and treatmentof thalassemia Hematopoietic Stem Cell Transplantation All children who have an HLA-matched sibling should be offered the option of bone marrow transplantation. Most success has been in children younger than 15 yr of age without excessive iron stores and hepatomegaly who undergo sibling HLA-matched allogeneic transplantation. In general, myeloablative conditioning regimens are required in order to prevent graft rejection and thalassemia recurrence.
- 41. Management and treatmentof thalassemia Splenectomy Splenectomy may be required in thalassemia patients who develop hypersplenism. These patients have a falling steady state haemoglobin and/or a rising transfusion requirement. Splenectomised children have risk of infections, venous thrombosis, pulmonary hypertension, leg ulcers, and silent cerebral infarction. All patients should be fully immunized against encapsulated bacteria and should be on long-term penicillin prophylaxis with appropriate instructions regarding fever management.
- 42. Preventative Monitoring ofThalassemia Patients Cardiac Serial echocardiograms should be monitored to evaluate cardiac function and pulmonary artery pressure. Pulmonary hypertension frequently occurs in non-transfused thalassemia patients and may be an indication for transfusion therapy. After 8 yr of chronic transfusion therapy, cardiac T2* MRI imaging studies are recommended. Patients with cardiac hemosiderosis and decreasing cardiac ejection fraction require intensive combination chelation therapy.
- 43. Preventative Monitoring ofThalassemia Patients Endocrine Iron deposition in the pituitary and endocrine organs can result in multiple endocrinopathies, including hypothyroidism, GH deficiency, delayed puberty, and hypoparathyroidism, diabetes mellitus, osteoporosis, and adrenal insufficiency. Monitoring starts by 5 yr of age, or after at least 3 yr of chronic transfusions. All children require monitoring of their height, weight, and sitting height semi-annually. Nutritional assessments are required. Most patients need vitamin D, calcium, vitamin B, vitamin C, and zinc replacement. Fertility is a growing concern among patients and should be assessed routinely.
- 44. Preventative Monitoring ofThalassemia Patients Psychosocial Support Thalassemia imposes major disruption in the family unit and significant obstacles to normal development. Culturally sensitive anticipatory counselling is necessary. Consultation to address financial and social issues is needed.
- 45. α-Thalassemia syndromes Thedeletion of 1 α-globin gene allele (silent trait) is not identifiable hematologically. The deletion of 2 α-globin gene alleles results in α-thalassemia trait. The α- globin alleles can be lost in a trans-(−α/−α) or cis- (α,α/--) configuration. α-Thalassemia trait manifest as a microcytic anemia that can be mistaken for iron-deficiency anemia. The haemoglobin analysis is normal, except during the newborn period, when Hb Bart is commonly <8% but >3%. The simplest approach to distinguish between iron deficiency and α- thalassemia trait is with a good dietary history. A brief course of iron supplementation along with monitoring of erythrocyte parameters might confirm the diagnosis of iron deficiency.
- 46. α-Thalassemia syndromes Thedeletion of 3 α-globin gene alleles leads to the diagnosis of HbH disease. The simplest manner of diagnosing HbH disease is during the newborn period, when excess in γ-tetramers are present and Hb Bart is commonly >25%. Later in childhood, there is an excess of β-globin chain tetramers that results in HbH(β4). A definitive diagnosis of HbH disease requires DNA analysis with supporting evidence. Patients with HbH disease have a marked microcytosis, anemia, mild splenomegaly, and, occasionally, scleral icterus or cholelithiasis. Chronic transfusion is not commonly required for therapy because the range of hemoglobin is 7-11 g/dL, with MCV 51-73 fL but intermittent transfusions for worsening anemia may be needed.
- 47. α-Thalassemia syndromes Thedeletion of all 4 α-globin gene alleles causes profound anemia during fetal life, resulting in hydrops fetalis. The ζ-globin gene must be present for fetal survival. There are no normal hemoglobins present at birth (primarily Hb Bart, with Hb Gower 1, Gower 2, and Portland). If the fetus survives, immediate exchange transfusion is indicated. At-risk couples for hydrops fetalis should be identified and offered molecular diagnosis on fetal tissue obtained early in pregnancy. Later in pregnancy, intrauterine transfusion can improve fetal survival, but chronic transfusion therapy or bone marrow transplantation for survivors will be required.
- 50. After iron chelationBeforeiron chelation
- 51. D/D based onred cell indices b-thal trait IDA Hb N/ RBC count MCV MCH MCHC N RDW N
- 52. NESTROFT Naked Eye SingleTube Reduced Osmotic Fragility Test 20ml of blood + 5 ml 0.36% buffered saline Mix and observe for reduced fragility This can serve as an initial screening process if electronic measurement of MCV is not available
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